CN103735492A - Progesterone vaginal expansive suppository as well as preparation method and detection method thereof - Google Patents
Progesterone vaginal expansive suppository as well as preparation method and detection method thereof Download PDFInfo
- Publication number
- CN103735492A CN103735492A CN201310750944.6A CN201310750944A CN103735492A CN 103735492 A CN103735492 A CN 103735492A CN 201310750944 A CN201310750944 A CN 201310750944A CN 103735492 A CN103735492 A CN 103735492A
- Authority
- CN
- China
- Prior art keywords
- progesterone
- expansible plug
- weight
- vagina expansible
- swell value
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Landscapes
- Medicinal Preparation (AREA)
- Measuring And Recording Apparatus For Diagnosis (AREA)
Abstract
The invention relates to a progesterone vaginal expansive suppository as well as a preparation method and a detection method thereof. The expansive suppository consists of a medicated substrate consisting of progesterone and a substrate as well as an expansion carrier, wherein the medicated substrate further contains cross-linked glucan gel, sodium carboxymethyl cellulose, monolauroyl glycerol, diacetin, glycerol and sodium citrate, and a clathrate compound is formed from the cross-linked glucan gel, sodium carboxymethyl cellulose and progesterone. The progesterone vaginal expansive suppository disclosed by the invention has the beneficial effects of high bioavailability, uniform dispersion of medicine and the like.
Description
Technical field
The invention belongs to vaginal suppository field, particularly a kind of Progesterone vagina expansible plug and preparation method thereof and detection method.
Background technology
Progesterone, chemistry DELTA4-pregn-3,20-dione by name, it is the crystalline powder of white or off-white color; Odorless, tasteless; Soluble in chloroform, in ethanol, ether, vegetable oil, dissolve, insoluble in water; Progesterone is a kind of natural progestogen of being secreted by corpus luteum, and the endometrium in vivo estrogen being excited has remarkable Morphology Effects; To maintain the necessary a kind of hormone of gestation; For the reactivity of the amenorrheas such as threatened abortion, habitual abortion or amenorrhea reason, diagnose clinically.
Existing progesterone preparation comprises Progesterone oral formulations, injection and suppository, because suppository does not have the side effect of oral formulations and injection, so is widely used; Chemical drugs terrestrial reference rises the 2nd of GB and has recorded Progesterone bolt, clinically for menoxenia, as the treatment of amenorrhea and dysfunctional uterine hemorrhage, inadequate luteal function, threatened abortion and habitual abortion (because of CLI causer), premenstrual tension syndrome; Due to the poorly water-soluble of Progesterone, the absorption difference of vaginal mucosa, so the suppository bioavailability of making is poor; The content of Progesterone is little in progesterone suppository, cause disperseing inhomogeneous, thereby suppository enters after vagina, the drug level difference of vaginal mucosa different piece is very large; And common Progesterone bolt also exists not easy to clean, easy pollution clothes; Active component and people's contact level are little, cause absorbing insufficient, do not bring into play the technical problems such as optimum curative effect of prescription.
Summary of the invention
In order to solve the problems of the technologies described above, give full play to the curative effect of Progesterone bolt, make the dispersion of Progesterone in bolt more even, the invention provides a kind of Progesterone vagina expansible plug and preparation method thereof; A kind of science detection method that can control above-mentioned Progesterone vagina expansible plug product quality is also provided simultaneously.
The concrete technical scheme of the present invention is as follows:
The invention provides a kind of Progesterone vagina expansible plug, this expansible plug comprises that weight portion is the Progesterone of 1-5 part, weight portion is the substrate of 60-195 part and the expandable expansion carrier that weight portion is 70-400 part, described Progesterone and substrate formed pastille substrate are coated in expansion carrier surface, and the swell value of described expansion carrier after saturated water suction is greater than 1.1;
Wherein, substrate comprises one or more in Acrawax, natural acid ester, lipoidis substrate, water-soluble base, hydrogenated oil and fat, glyceride or distillate oil;
Acrawax comprises one or more in mixed fatty glycerides, propylene glycol stearate, fixed oil, semi-synthetic fatty acid glyceride, semi-synthetic cocos nucifera oil ester, Witepsol, semi-synthetic Petiolus Trachycarpi grease or semi-synthetic Fructus Litseae ester;
Natural acid ester comprises one or more in oleum sapii, Oleum Linderae, Fructus Foeniculi fat, Ke Kemu fat or cocoa butter;
Lipoidis substrate comprises lanoline or lanonol;
Water-soluble base comprises one or more in PEG400, polyethylene glycol 1500, Macrogol 4000, polyethylene glycol 6000, glycerin gelatine, polysorbate60, polysorbate65, polyoxyethylene condensation substance Idropostal, polyoxyethylene monostearate or poloxamer;
Hydrogenated oil and fat comprises one or more in hydrogenated vegetable oil, hydrogenated groundnut, castor oil hydrogenated or cotmar;
Glyceride comprises Adeps Solidus, Massa Estarinum A, Massa Estarinum AS, Massa Estarinum B, Massa Estarinum C, Massa Estarinum D, Massa Estarinum E, Massa Estarinum I, Massa Estarinum T, Massa Mf13, Suppository Base W, Suppository Base AB, Suppository Base A, Suppository Base B, Suppository Base BC, Suppository Base BD, Suppository Base BBC, Suppository Base E, Suppository Base BCF, Suppository Base C, Suppository Base D, Suppository Base299, Wecobee W, Wecobee K, Wecobee S, Wecobee M, Wecobee ES, Massuppol, Massuppol15, Suppocire OSI, Suppocire OSIx Suppocire A, Suppocire B, Suppocire C, Suppocire D, Suppocire DM, Suppocire H, Suppocire L, Tegester Triglyceride Bases-9, Tegester Triglyceride Bases-MA, one or more in Tegester Triglyceride Bases-57,
Distillate oil comprises fractional distillation Petiolus Trachycarpi oil or fractionated coconut oil;
Preferably, substrate comprises one or more in Acrawax, natural acid ester or water-soluble base.
The substrate of English name of the present invention is included (L. La Heman in < < industrial pharmacy theory and practice > > book, H.A. sharp Berman, J.L. block Buddhist nun uncommon. industrial pharmacy theory and practice, Chemical Industry Press, second edition: 215-217).
The present invention has adopted original creation " intravaginal sticking type medicine-feeding technology ", and this technology by adding expansion carrier to realize in suppository.Ordinary suppository is due to the relation of gravity, no matter user be standing, sitting posture or lie under formula position, always have vagina can not or the less pastille substrate that touches, after expansion carrier expands, pastille substrate can be 360 ° and contact with vaginal walls, fully administration, 6 times of administration enlarged areas, medicine directly attaches to lesions position, makes the position that originally cannot contact medicine also can obtain effectively attaching treatment; In addition, " anti-side leakage key " design concept has been applied in the introducing of expansion carrier, because the expansion of expansion carrier tail end (non-pastille substrate) can be close to vaginal wall, and then prevent the outflow of medicine and substrate, reduce the pollution of medicated clothing and keep the valid density of medicine; And by " inner core coefficient of expansion control technology ", the swell value of carrier after saturated water suction that can make to expand is greater than 1.1.
Further improve the mixture of matrix optimization natural acid ester of the present invention and water-soluble base; The ratio of weight and number of natural acid ester and water-soluble base is 1:15-21; Preferably, natural acid ester is Oleum Linderae, and water-soluble base is glycerin gelatine, and the ratio of weight and number of described Oleum Linderae and glycerin gelatine is 1:17.5.In water-soluble base, add a certain amount of natural acid ester can improve melting of expansible plug and become the time limit.
Further improve, pastille substrate of the present invention also comprises that weight portion is that sephadex and the weight portion of 7-15 part is the sodium carboxymethyl cellulose of 1-5 part.In wherein the mixture of sephadex and sodium carboxymethyl cellulose can be wrapped in Progesterone, improve the water solublity of Progesterone, and then improve the bioavailability of expansible plug.
Further improve, pastille substrate of the present invention also comprises that weight portion is the lauric monoglyceride of 5-20 part.Wherein, lauric monoglyceride is more conducive to the dispersion of Progesterone, improves the uniformity of dosage units of expansible plug, makes expansible plug bring into play more equably curative effect.
In order to improve the denseness of each composition in expansible plug, pastille substrate of the present invention also comprises that weight portion is the Glycerine 1,3-diacetate of 2-8 part.
Further improve, the pastille substrate in expansible plug also comprises that weight portion is that glycerol and the weight portion of 0.2-1.5 part is the sodium citrate of 1-5 part.Wherein glycerol can increase the lubricity of expansible plug, plays the effect of moisturizing; Sodium citrate can play the effect of stabilizing agent.
Further improve, the parts by weight of each composition of expansible plug of the present invention are preferably:
Preferably, the swell value of expansion carrier of the present invention after saturated water suction is greater than 1.5, and swell value is swell value radially; Expansion carrier includes but not limited to cotton sliver, also can comprise the sterilizable material that other can expand, as non-woven fabrics, elastic fiber etc.
Pastille substrate of the present invention is the front end 1/5-4/5 place that Semi surrounding type is coated in expansion carrier, according to " human engineering suppository " shape, be designed to the shapes such as duckbill, oval, spherical, avette, bullet shaped, torpedo, cylindrical, taper shape or clavate.
The expansion carrier rear end of Progesterone vagina expansible plug of the present invention is connected with bracing wire, suppository after expansion, by the rear end bracing wire of tractive expansion carrier, be adsorbed on dead bark on expansion carrier and also pull out in the lump externally, this expansible plug belongs to " integrated dosage form is cleaned in treatment ".
In order to reach Progesterone vagina expansible plug of the present invention, meet the effect that water can expand rapidly, after the water suction of expansion carrier, the maximum water absorption of every is not less than 1.5 milliliters; Suitable water absorption, can guarantee suitable swell value, and too low or too high water absorption all can cause bad impact.When water absorption is too low, can not guarantee that Progesterone vagina expansible plug of the present invention meets the feature that water expand and make to expand insufficient; When water absorption is too high, expansion carrier is understood too much absorption ingredient and is limited its diffusion; Therefore, water absorption is too low or too high, is not the desired expansion carrier of the present invention.
The present invention provides the preparation method of Progesterone vagina expansible plug on the other hand, and the method comprises the steps:
1) preparation of pastille substrate:
A. substrate is placed in to water-bath heating and melting, under stirring, adds glycerol, mix homogeneously, makes fused mass;
B. sephadex and sodium carboxymethyl cellulose are added in mortar, be fully ground to pastel, continue to grind, add Progesterone, grind evenly, make clathrate;
C. lauric monoglyceride is dissolved in ethanol, stirs, then add clathrate, mix homogeneously, spraying is dry, makes the first mixture;
D. the first mixture and Glycerine 1,3-diacetate and sodium citrate mixture is even, make the second mixture;
E. the second mixture is added in the fused mass of step a, mix homogeneously, makes pastille substrate;
2) preparation of expansible plug: pastille substrate is poured in bolt mould, inserted expansion carrier, cooling and shaping, makes suppository.
The preparation method of Progesterone vagina expansible plug of the present invention has adopted " the integrally formed technology of the disposable fill of stype ".
The present invention also provides the detection method of Progesterone vagina expansible plug on the other hand, and this detection method comprises swell value assay method, weight differential detection method, assay etc.
Wherein swell value assay method comprises:
A. along radially the choosing a bit or some points of described Progesterone vagina expansible plug end face, measure the initial length H of described expansion carrier;
B. after the saturated water suction of described Progesterone vagina expansible plug, be determined at the rear length h of selected location place's expansion carrier expansion in a step;
While c. calculating described swell value, according to I formula, calculate;
（I）
Wherein, p represent axial swell value, h represent to expand after length, H represent initial length; Or described swell value assay method is as follows:
D. along described Progesterone vagina expansible plug axially choose a place or some positions, measure the initial diameter R of described expansion carrier;
E. after the saturated water suction of described Progesterone vagina expansible plug, be determined at the rear diameter r of selected location place's expansion carrier expansion in d step;
While f. calculating described swell value, by II formula, calculate;
（II）
Wherein, P represent swell value, r radially represent to expand after diameter, R represent initial diameter; Described weight differential assay method comprises:
G. get described Progesterone vagina expansible plug, take weight M;
H. get the expansion carrier in the described Progesterone vagina expansible plug that scrapes pastille substrate, dry, take weight m, according to the weight X of pastille substrate as described in calculating as III formula:
X=M-m
（Ⅲ）。
Further, in the detection method of Progesterone vagina expansible plug of the present invention, melt and become after time limit detection, then carry out following at least one detection method:
1) swell value assay method is as follows:
A. first along radially the choosing a bit or some points of described Progesterone vagina expansible plug end face, measure after the initial length H of described expansion carrier, then the different angles of rolling measure several times, Hi averages;
B. described Progesterone vagina expansible plug melts after the detection of change time limit, is determined at the rear length h of selected location place's expansion carrier expansion in a step; The different angles of rolling are again measured several times, ask the rear average length hi that expands;
While c. calculating described swell value, according to I formula, calculate;
（I）
Wherein, pi represent axial swell value, hi represent to expand after average length, Hi represent average initial length;
Or described swell value assay method is as follows:
D. first an angle along described Progesterone vagina expansible plug axially choose a place or some positions, measure after the initial diameter R of described expansion carrier, then the different angles of rolling measure several times, Ri averages;
E. described Progesterone vagina expansible plug melts after the detection of change time limit, is determined at the rear diameter r of selected location place's expansion carrier expansion in d step; The different angles of rolling are again measured several times, ask the rear average diameter ri that expands;
While f. calculating described swell value, by II formula, calculate;
（II）
Wherein, Pi represent swell value, ri radially represent to expand after average diameter, Ri represent average initial diameter.
The wherein said change time limit assay method (two appendix of existing Chinese Pharmacopoeia) that melts comprising: gets 3 of described Progesterone vagina expansible plugs, in room temperature, places after 1 hour, be placed on respectively on lower floor's plectane of 3 metal rack, pack in sleeve pipe separately, and fixing with hook.Unless otherwise specified, said apparatus is dipped vertically into respectively in the container that fills 37.0 ± 0.5 ℃ of water that are no less than 4L, its upper end position should fill a rot at 90mm place, underwater in container, every 10 minutes, overturn this device once in solution.Above numerical range should not be construed as limitation of the present invention, and the technical scheme in above-mentioned numerical range is not in protection scope of the present invention yet.
2) weight differential assay method:
G. get described Progesterone vagina expansible plug, take weight M;
H. scrape pastille substrate, expansion carrier is placed in to 20-90 ℃ of organic solvent, take out, in 50-150 ℃ of dry 1-10h, take weight m, according to the weight X of pastille substrate as described in the calculating of III formula
X=M-m（Ⅲ）
Wherein, described organic solvent is selected from one or more in ethanol, methanol or isopropyl alcohol.
Further, in the detection method of Progesterone vagina expansible plug of the present invention, expansion carrier is cotton sliver, and detection method comprises following at least one method:
1) swell value assay method:
Get 3 of Progesterone vagina expansible plugs, with slide gauge, survey its afterbody cotton sliver diameter, roll approximately 90 ° and survey once again, survey twice for every, obtain 2 meansigma methods Ri of every mensuration; Above-mentioned 3 bolts are used for melting and become after the time limit measures and finish, take out immediately residue cotton sliver, treat disconnected of water, all gently be placed on glass plate, with slide gauge, measure two ends and middle three positions of each cotton sliver, roll after approximately 90 ° and measure three positions again, each cotton sliver obtains six data altogether, obtains 6 meansigma methods r of mensuration
i, calculate the swell value P of every
i, the swell value of three bolts all should be greater than 1.5.
2) weight differential assay method:
Get 10 of Progesterone vagina expansible plugs, the accurately weighed weight of difference, gently scrape pastille substrate (must not lose cotton sliver), cotton sliver is placed in to the 200-400ml ethanol of 50-80 ℃, preferably, cotton sliver is placed in to the 300ml ethanol of 60-70 ℃, and 80khz frequency ultrasonic cleaning 5 minutes, the remaining stromatolysis in cotton sliver surface is removed, taking out cotton sliver firmly extracts, with filter paper, inhale 3 times again, in 105 ℃, be dried 2 hours, take out, room temperature was placed after 1 hour, the accurately weighed cotton sliver weight of difference, obtain every pastille substrate weight and average pastille substrate weight, every pastille substrate weight and average pastille substrate weight ratio are, what exceed average pastille substrate weight ± 10% must not be more than 2, and must not there is 1 times of 1 overrun.
The assay method of the swell value of Progesterone vagina expansible plug provided by the present invention adopts repeatedly measuring method of multi-angle, has improved the accuracy of measuring, and has increased the operability of measuring, and method is easier to judgement; When carrying out the standard detection Progesterone vagina of the present invention expansible plug of state-promulgated pharmacopoeia appendix weight differential, substrate need be scraped off, the scraping degree of grasping due to operator is different, cause every scraping degree difference larger, so the present invention adopts the substrate on dissolution with solvents expansible plug surface, through verification experimental verification, when adopting hot ethanol to clean the substrate on expansible plug surface, result is better, and repeatability is higher, and weight differential assay method is more convenient stable.
Content assaying method is according to Chinese Pharmacopoeia appendix IV A spectrophotometry, and assay method is as follows:
Get 10 of Progesterone vagina expansible plugs, accurately weighed, be cut into broken end, precision takes in right amount (being approximately equivalent to Progesterone 5mg), adds anhydrous alcohol solution and is quantitatively diluted to the solution that approximately contains 10 μ g in every 1ml, according to spectrophotography, wavelength place at 241nm measures trap, by C
21h
30o
2absorptance (E1% 1cm) be 540 calculating, obtain.
Progesterone vagina expansible plug provided by the present invention has evident in efficacy, the active component beneficial effect such as be uniformly dispersed, and this Progesterone vagina expansible plug has adopted six leading technologies of original creation, expansion carrier in described Progesterone vagina expansible plug add " the disposable fill of stype is integrally formed " technology of having applied original creation, " control of the inner core coefficient of expansion " technology, " human engineering bolt type " technology, " treatment is clean integrated " dosage form, " administration of intravaginal sticking type " technology, " anti-side leakage key design " six technology, this expansion carrier can make the pastille substrate of Progesterone vagina expansible plug fully contact with vaginal walls, and prevent medicinal liquid outflow, the present invention adds sephadex and sodium carboxymethyl cellulose in pastille substrate, can make clathrate with Progesterone, and Progesterone is wrapped in mixture, can improve the water solublity of Progesterone, improves the bioavailability of expansible plug, in pastille substrate, also add lauric monoglyceride, it can play the effect that disperses Progesterone simultaneously, further improves the uniformity of dosage units of Progesterone vagina expansible plug, can act on sufficiently uniformly vagina, further in pastille substrate, add Glycerine 1,3-diacetate, glycerol and sodium citrate, the mixing and the denseness that have improved each composition in expansible plug increased the lubricity of expansible plug, and the expansible plug of making have good moistening effect to vagina simultaneously.
Accompanying drawing explanation
The schematic diagram of Fig. 1 and Fig. 2 swell value assay method.
The specific embodiment
Embodiment 1
Preparation method:
1) preparation of pastille substrate:
A. Oleum Linderae and glycerin gelatine are placed in to water-bath heating and melting, make fused mass;
B. Progesterone is added in the fused mass of step a, mix homogeneously, makes pastille substrate;
2) preparation of expansible plug: pastille substrate is poured in bolt mould, inserted cotton sliver, cooling and shaping, makes 100 pieces of spherical suppositorys, every piece of heavily about 3.4g.
Embodiment 2
Preparation method:
1) preparation of pastille substrate:
A. semi-synthetic fatty acid glyceride is placed in to water-bath heating and melting, makes fused mass;
B. sephadex and sodium carboxymethyl cellulose are added in mortar, be fully ground to pastel, continue to grind, add Progesterone, grind evenly, make clathrate;
C. clathrate is added in the fused mass of step a, mix homogeneously, makes pastille substrate;
2) preparation of expansible plug: pastille substrate is poured in bolt mould, inserted cotton sliver, cooling and shaping, makes 100 pieces of cylinder suppositorys, every piece of heavily about 1.4g.
Embodiment 3
Preparation method: make 100 pieces of torpedo suppositorys by the method for embodiment 2, every piece of heavily about 5.0g.
Embodiment 4
Preparation method:
1) preparation of pastille substrate:
A. oleum sapii and polyoxyethylene list hard acid ester are placed in to water-bath heating and melting, make fused mass;
B. sephadex and sodium carboxymethyl cellulose are added in mortar, be fully ground to pastel, continue to grind, add Progesterone, grind evenly, make clathrate;
C. lauric monoglyceride is dissolved in ethanol, stirs, then add clathrate, mix homogeneously, spraying is dry, makes the first mixture;
D. the first mixture is added in the fused mass of step a, mix homogeneously, makes pastille substrate;
2) preparation of expansible plug: pastille substrate is poured in bolt mould, inserted cotton sliver, cooling and shaping, makes 100 pieces of clavate suppositorys, every piece of heavily about 3.8g.
Embodiment 5
Preparation method: make 100 pieces of oval suppositorys by the method for embodiment 4, every piece of heavily about 4.4g.
Embodiment 6
Preparation method:
1) preparation of pastille substrate:
A. Fructus Foeniculi fat and poloxamer are placed in to water-bath heating and melting, make fused mass;
B. sephadex and sodium carboxymethyl cellulose are added in mortar, be fully ground to pastel, continue to grind, add Progesterone, grind evenly, make clathrate;
C. lauric monoglyceride is dissolved in ethanol, stirs, then add clathrate, mix homogeneously, spraying is dry, makes the first mixture;
D. the first mixture and Glycerine 1,3-diacetate mixture is even, make the second mixture;
E. the second mixture is added in the fused mass of step a, mix homogeneously, makes pastille substrate;
2) preparation of expansible plug: pastille substrate is poured in bolt mould, inserted cotton sliver, cooling and shaping, makes 100 pieces of avette suppositorys, every piece of heavily about 3.1g.
Embodiment 7
Preparation method:
1) preparation of pastille substrate:
A. Oleum Linderae and glycerin gelatine are placed in to water-bath heating and melting, under stirring, add glycerol, mix homogeneously, makes fused mass;
B. sephadex and sodium carboxymethyl cellulose are added in mortar, be fully ground to pastel, continue to grind, add Progesterone, grind evenly, make clathrate;
C. lauric monoglyceride is dissolved in ethanol, stirs, then add clathrate, mix homogeneously, spraying is dry, makes the first mixture;
D. the first mixture and Glycerine 1,3-diacetate and sodium citrate mixture is even, make the second mixture;
E. the second mixture is added in the fused mass of step a, mix homogeneously, makes pastille substrate;
2) preparation of expansible plug: pastille substrate is poured in bolt mould, inserted cotton sliver, cooling and shaping, makes 100 pieces of duckbill suppositorys, every piece of heavily about 3.4g.
Embodiment 8
Preparation method: make 100 pieces of bullet shaped suppositorys by the method for embodiment 7, every piece of heavily about 2.5g.
Embodiment 9
Preparation method: make 100 pieces of circular cone suppositorys by the method for embodiment 7, every piece of heavily about 3.8g.
Test example 1 uniformity of dosage units detects test
Uniformity of dosage units detection method referring to: with reference to 2010 editions < < Chinese Pharmacopoeia > > appendix XE uniformity of dosage units detection methods.
Get each 10 pieces of the Progesterone vagina expansible plug of embodiment 4-9 and commercially available Progesterone vaginal suppositories, by content assaying method, measure every piece and take the relative amount X that labelled amount is 100, and calculate meansigma methods
absolute value with the difference of standard deviation S and labelled amount and average
measurement result is in Table 1;
The uniformity of dosage units testing result of table 1 embodiment 4-9 and commercially available Progesterone bolt
The A+1.80S value of the Progesterone vagina expansible plug of embodiment 4-9 is significantly less than common Progesterone bolt as shown in Table 1, the uniformity of dosage units that shows the Progesterone vagina expansible plug in above-described embodiment 4-9 is conformance with standard not only, and the uniformity of dosage units of Progesterone vagina expansible plug of the present invention is compared and significantly improved with common Progesterone bolt.
Test example 2 stability tests
1. accelerated test: the Progesterone vagina expansible plug of getting embodiment 7, be divided into 3 batches, at 25 ℃ ± 2 ℃ of temperature, relative humidity is to place 6 months under 65% ± 5% condition, respectively at sampling in 1 month, 2 months, 3 months, 6 months once, investigate the character, color and luster of expansible plug, containing the amount (labelled amount %) of Progesterone, melt and become time limit, related substance equistability index, result has no significant change.
2. long term test: the Progesterone vagina expansible plug of getting embodiment 7, be divided into 3 batches, in temperature, be at 25 ℃ ± 2 ℃, relative humidity is to place 12 months under 60% ± 10% condition, respectively at sampling in 0 month, 3 months, 6 months, 9 months, 12 months, detect the character of expansible plug, containing the amount (labelled amount %) of Progesterone, melt indexs such as becoming time limit and related substance, be showed no significant change.
Test example 3 swell values are measured
Method one
Get 3 of Progesterone vagina expansible plugs, with slide gauge, survey its afterbody cotton sliver diameter, roll approximately 90 ° and survey once again, survey twice for every, obtain 2 meansigma methods Ri of every mensuration; Above-mentioned 3 bolts are used for melting and become after the time limit measures and finish, take out immediately residue cotton sliver, treat disconnected of water, all gently be placed on glass plate, with slide gauge, measure two ends and middle three positions of each cotton sliver, roll after approximately 90 ° and measure three positions again, each cotton sliver obtains six data altogether, obtains 6 meansigma methods r of mensuration
i, calculate the swell value P of every
i, the swell value of three bolts is all greater than 1.5.
As shown in table 2 according to the swell value of the Progesterone vagina expansible plug of above-mentioned swell value assay method mensuration embodiment 1-9;
The swell value of table 2 embodiment 1-9 Progesterone vagina expansible plug
| Embodiment | Average diameter (mm) before expanding | Average diameter (mm) after expanding | Swell value (doubly) | Result |
| Embodiment 1 | 12.11 | 22.47 | 1.85 | Qualified |
| Embodiment 2 | 12.03 | 20.08 | 1.67 | Qualified |
| Embodiment 3 | 11.82 | 21.43 | 1.81 | Qualified |
| Embodiment 4 | 11.94 | 20.19 | 1.69 | Qualified |
| Embodiment 5 | 12.16 | 22.87 | 1.88 | Qualified |
| Embodiment 6 | 12.24 | 23.32 | 1.91 | Qualified |
| Embodiment 7 | 11.83 | 21.04 | 1.78 | Qualified |
[0162]?
| Embodiment 8 | 12.08 | 22.26 | 1.84 | Qualified |
| Embodiment 9 | 11.99 | 21.91 | 1.83 | Qualified |
Method two
As depicted in figs. 1 and 2:
1) swell value assay method:
A. first along described vagina expansible plug end face, radially choose C1, C2, tri-points of C3, with slide gauge, measure after initial length H1, H2, the H3 of described expansion carrier, the 90 ° of measurements of rolling again, radially choose C1, C4, tri-points of C5 along described vagina expansible plug end face are measured after initial length H4, H5, the H6 of described expansion carrier with slide gauge, ask the meansigma methods Hi of H1, H2, H3, H4, H5 and H6;
B. described vagina expansible plug melts after the detection of change time limit, with slide gauge, is determined at selected C1, C2 in a step, C3 tri-expansions of position expansion carriers rear length h1, h2, h3; Roll again 90 °, with slide gauge, be determined at selected C1, C4 in a step, C5 tri-expansions of position expansion carriers rear length h4, h5, h6, ask the average length of h1, h2, h3, h4, h5 and h6, be the rear average length hi that expands;
While c. calculating described swell value, according to I formula, calculate;
（I）
Wherein, pi represent axial swell value, hi represent to expand after average length, Hi represent average initial length;
Or, swell value assay method:
D. first an angle, along described vagina expansible plug, axially choose A1, A2 and tri-points of A3, with slide gauge, measure after initial diameter R1, the R2 and R3 of described expansion carrier, roll again 90 °, along described vagina expansible plug, axially choose B1, B2 and tri-points of B3, with slide gauge, measure after initial diameter R4, the R5 and R6 of described expansion carrier, ask the meansigma methods Ri of R1, R2, R3, R4, R5 and six initial diameters of R6;
E. described vagina expansible plug melts and becomes after the time limit detects, and after being determined in d step selected A1, A2 and A3 position expansion carrier and expanding, diameter is respectively r1, r2 and r3; Roll again 90 ° measure in d step selected B1, B2 and B3 position expansion carrier and expand after diameter be respectively r4, r5 and r6, ask the meansigma methods of r1, r2, r3, r4, r5 and r6, average diameter ri afterwards must expand;
While f. calculating described swell value, by II formula, calculate;
（II）
Wherein, Pi represent swell value, ri radially represent to expand after average diameter, Ri represent average initial diameter.
Test example 4 weight differential determination tests
Get 10 of Progesterone vagina expansible plugs, the accurately weighed weight of difference, gently scrape pastille substrate (must not lose cotton sliver), cotton sliver is placed in to the 300ml ethanol of 60-70 ℃, if (substrate comprises glycerin gelatine, cotton sliver is placed in to the 300ml water of 60-70 ℃), and 80khz frequency ultrasonic cleaning 5 minutes, the remaining stromatolysis in cotton sliver surface is removed, taking out cotton sliver firmly extracts, with filter paper, inhale 3 times again, in 105 ℃, be dried 2 hours, take out, room temperature was placed after 1 hour, the accurately weighed cotton sliver weight of difference, obtain every pastille substrate weight and average pastille substrate weight, every pastille substrate weight and average pastille substrate weight ratio are, what exceed average pastille substrate weight ± 10% must not be more than 2, and must not there is 1 times of 1 overrun.
Repeat aforesaid operations, detect the Progesterone vagina expansible plug of embodiment 1-9, the equal conformance with standard of its weight differential.
Test example 5
1. MethodsThe cases enrolled: patient's 35 examples of selecting menoxenia; Main suit: menoxenia or amenorrhea; Blood progesterone level ﹤ 7nmol/L is surveyed in menstruation latter half; Endometrial biopsy turns out to be anovular menstruation person; Get rid of the patient of other diseases and get rid of the patient who received gonadotherapy within March;
2. grouping and administration: 50 routine menoxenia patients are divided into treatment group 28 examples at random, matched group 22 examples; Treatment group gives the Progesterone vagina expansible plug of embodiment 7, and matched group gives commercially available Progesterone bolt; Two groups of medicines are all placed in 1 piece of intravaginal every day of patient, within 7 days, are a course for the treatment of;
3. observe treatment
1) observation of curative effect:
Hormone determination: blood FSH, LH, E2, P, T, PRL concentration are measured in before treatment and treatment first three sky the 3rd course for the treatment of;
Before treatment and the 3rd course for the treatment of end get endometrium specimen and carry out histological examination;
2) safety is observed
Before and after treatment, measure respectively routine blood test, liver, renal function;
4. curative effect judgement
1) blood progesterone level changes
Alleviate ﹥ 32nmol/L completely
Effective 20-32nmol/L
Effective 7-19nmol/L
Invalid ﹤ 7nmol/L
2) endomentrial morphology changes
Alleviate completely: endometrium is secretory reaction;
Effective: endometrium is early secretory reaction or hyposecretion
Invalid: endometrium is proliferation response;
5. result
1. the blood progesterone level grouped comparison after treatment group and treatment of control group is in Table 3;
Table 3 liang group blood progesterone level comparison
The 3rd course for the treatment of, finish to check for first 3 days as can be seen from the table, treatment group blood progesterone level raises, and looked into the rear level of ovulation, and curative effect is better than matched group.
2. treatment group and matched group endomentrial morphology evaluation result are in Table 4;
The endomentrial morphology Assessment of Changes of table 4 liang group
After treatment finishes as can be seen from the table, endometrial biopsy analyzing specimen shows, the effective percentage for the treatment of group and matched group reaches respectively 90.5% and 81.2%, and through relatively, two groups of curative effects have diversity.
6. conclusion
Above experimental result shows, Progesterone vagina expansible plug of the present invention absorbs good, can significantly improve progesterone level.And act on endometrium and make it to be converted into secretory reaction by hypertrophy; Show that this expansible plug can improve the symptom of patient's menoxenia effectively.
Test example 6 toxicological studies
1. acute toxicity test: Cavia porcellus intravaginal gives the Progesterone vagina expansible plug of the embodiment of the present invention 7, giving dosage is 180 times of clinical consumption per days, dosing time, Continuous Observation 10 days, the all Cavia porcelluss of result are strong deposits, and diet, activity, hair, Excreta are all no abnormal;
2. long term toxicity test: the Progesterone vagina expansible plug of the embodiment of the present invention 7 is placed in to Cavia porcellus intravaginal, administration 4 weeks, result shows, Progesterone vagina expansible plug of the present invention on the body weight of Cavia porcellus, hemogram, liver, renal function all without impact, pathologic finding to the heart, liver, spleen, lung, kidney, uterus, also without significant change.
3. mucomembranous pungency test: the Progesterone vagina expansible plug of the embodiment of the present invention 7 is placed in rabbit vagina, once a day, dispensing is 10 days continuously, observe, after last administration 24 hours, the secretions of observing rabbit vagina has or not the signs such as abnormal and feed, hair color, mental status, all without significant reaction, put to death animal and take out vaginal mucosa naked eyes and Microscopic observation, being showed no mucosa has the symptoms such as hyperemia, ulcer and inflammation to occur.
The above results shows, the acute toxicity of Progesterone vagina expansible plug and long term toxicity test and mucomembranous irritant test are showed no toxicity, and clinical practice is safe and reliable.
Claims (12)
1. a Progesterone vagina expansible plug, it is characterized in that, described expansible plug comprises that weight portion is the Progesterone of 1-5 part, weight portion is the substrate of 60-195 part and the expandable expansion carrier that weight portion is 70-400 part, described Progesterone and substrate formed pastille substrate are coated in expansion carrier surface, and the swell value of described expansion carrier after saturated water suction is greater than 1.1;
Described substrate comprises one or more in Acrawax, natural acid ester or water-soluble base;
Described Acrawax comprises one or more in mixed fatty glycerides, propylene glycol stearate, fixed oil, semi-synthetic fatty acid glyceride, semi-synthetic cocos nucifera oil ester, semi-synthetic Petiolus Trachycarpi grease or semi-synthetic Fructus Litseae ester;
Described natural acid ester comprises one or more in oleum sapii, Oleum Linderae, Fructus Foeniculi fat, Ke Kemu fat or cocoa butter;
Described water-soluble base comprises one or more in PEG400, polyethylene glycol 1500, Macrogol 4000, polyethylene glycol 6000, glycerin gelatine, polyoxyethylene monostearate or poloxamer.
2. Progesterone vagina expansible plug as claimed in claim 1, is characterized in that, described substrate is the mixture of natural acid ester and water-soluble base; The ratio of weight and number of described natural acid ester and water-soluble base is 1:15-21; Preferably, described natural acid ester is Oleum Linderae, and described water-soluble base is glycerin gelatine, and the ratio of weight and number of described Oleum Linderae and glycerin gelatine is 1:17.5.
3. Progesterone vagina expansible plug as claimed in claim 1, is characterized in that, described pastille substrate also comprises that weight portion is that sephadex and the weight portion of 7-15 part is the sodium carboxymethyl cellulose of 1-5 part.
4. Progesterone vagina expansible plug as claimed in claim 3, is characterized in that, described pastille substrate also comprises that weight portion is the lauric monoglyceride of 5-20 part.
5. Progesterone vagina expansible plug as claimed in claim 4, is characterized in that, described pastille substrate also comprises that weight portion is the Glycerine 1,3-diacetate of 2-8 part.
6. Progesterone vagina expansible plug as claimed in claim 5, is characterized in that, described pastille substrate also comprises that weight portion is that glycerol and the weight portion of 0.2-1.5 part is the sodium citrate of 1-5 part.
7. Progesterone vagina expansible plug as claimed in claim 6, is characterized in that, the parts by weight of described each composition of expansible plug are:
8. the Progesterone vagina expansible plug as described in as arbitrary in claim 1-7, is characterized in that, the swell value of described expansion carrier after saturated water suction is greater than 1.5, and described swell value is swell value radially; Described expansion carrier is cotton sliver; Described pastille substrate is the front end 1/5-4/5 place that Semi surrounding type is coated in described expansion carrier, and the rear end of described expansion carrier is connected with bracing wire; After described expansion carrier water suction, the maximum water absorption of every is not less than 1.5 milliliters.
9. the preparation method of Progesterone vagina expansible plug as claimed in claim 6, is characterized in that, described method comprises the steps:
1) preparation of pastille substrate:
A. substrate is placed in to water-bath heating and melting, under stirring, adds glycerol, mix homogeneously, makes fused mass;
B. sephadex and sodium carboxymethyl cellulose are added in mortar, be fully ground to pastel, continue to grind, add Progesterone, grind evenly, make clathrate;
C. lauric monoglyceride is dissolved in ethanol, stirs, then add clathrate, mix homogeneously, spraying is dry, makes the first mixture;
D. the first mixture and Glycerine 1,3-diacetate and sodium citrate mixture is even, make the second mixture;
E. the second mixture is added in the fused mass of step a, mix homogeneously, makes pastille substrate;
2) preparation of expansible plug: pastille substrate is poured in bolt mould, inserted expansion carrier, cooling and shaping, makes suppository.
10. as the detection method of the Progesterone vagina expansible plug of claim 1-7 or 9 as described in arbitrary, it is characterized in that, described detection method comprises following at least one method:
1) swell value assay method is as follows:
A. along radially the choosing a bit or some points of described Progesterone vagina expansible plug end face, measure the initial length H of described expansion carrier;
B. after the saturated water suction of described Progesterone vagina expansible plug, be determined at the rear length h of selected location place's expansion carrier expansion in a step;
While c. calculating described swell value, according to I formula, calculate;
（I）
Wherein, p represent axial swell value, h represent to expand after length, H represent initial length; Or swell value assay method is as follows:
D. along described Progesterone vagina expansible plug axially choose a place or some positions, measure the initial diameter R of described expansion carrier;
E. after the saturated water suction of described Progesterone vagina expansible plug, be determined at the rear diameter r of selected location place's expansion carrier expansion in d step;
While f. calculating described swell value, by II formula, calculate;
（II）
Wherein, P represent swell value, r radially represent to expand after diameter, R represent initial diameter;
2) weight differential assay method:
G. get described Progesterone vagina expansible plug, take weight M;
H. get the expansion carrier in the described Progesterone vagina expansible plug that scrapes pastille substrate, dry, take weight m, according to the weight X of pastille substrate as described in calculating as III formula:
X=M-m
（Ⅲ）。
The detection method of 11. Progesterone vagina expansible plugs as claimed in claim 10, is characterized in that, melts and becomes after time limit detection, then carry out following at least one detection method:
1) swell value assay method is as follows:
A. first along radially the choosing a bit or some points of described Progesterone vagina expansible plug end face, measure after the initial length H of described expansion carrier, then the different angles of rolling measure several times, Hi averages;
B. described Progesterone vagina expansible plug melts after the detection of change time limit, is determined at the rear length h of selected location place's expansion carrier expansion in a step; The different angles of rolling are again measured several times, ask the rear average length hi that expands;
While c. calculating described swell value, according to I formula, calculate;
（I）
Wherein, pi represent axial swell value, hi represent to expand after average length, Hi represent average initial length;
Or swell value assay method is as follows:
D. first an angle along described Progesterone vagina expansible plug axially choose a place or some positions, measure after the initial diameter R of described expansion carrier, then the different angles of rolling measure several times, Ri averages;
E. described Progesterone vagina expansible plug melts after the detection of change time limit, is determined at the rear diameter r of selected location place's expansion carrier expansion in d step; The different angles of rolling are again measured several times, ask the rear average diameter ri that expands;
While f. calculating described swell value, by II formula, calculate;
（II）
Wherein, Pi represent swell value, ri radially represent to expand after average diameter, Ri represent average initial diameter;
2) weight differential assay method:
G. get described Progesterone vagina expansible plug, take weight M;
H. scrape pastille substrate, expansion carrier is placed in to 20-90 ℃ of organic solvent, take out, in 50-150 ℃ of dry 1-10h, take weight m, according to the weight X of pastille substrate as described in the calculating of III formula
X=M-m（Ⅲ）
Wherein, described organic solvent is selected from one or more in ethanol, methanol or isopropyl alcohol.
The detection method of 12. Progesterone vagina expansible plugs as claimed in claim 11, is characterized in that, described expansion carrier is cotton sliver, and described detection method comprises following at least one method:
1) swell value assay method:
Get 3 of described Progesterone vagina expansible plugs, with slide gauge, survey its afterbody cotton sliver diameter, roll approximately 90 ° and survey once again, survey twice for every, obtain 2 meansigma methods Ri of every mensuration; Above-mentioned 3 bolts are used for melting and become after the time limit measures and finish, take out immediately residue cotton sliver, treat disconnected of water, all gently be placed on glass plate, with slide gauge, measure two ends and middle three positions of each cotton sliver, roll after approximately 90 ° and measure three positions again, each cotton sliver obtains six data altogether, obtains 6 meansigma methods r of mensuration
i, calculate the swell value P of every
i, the swell value of three bolts all should be greater than 1.5;
2) weight differential assay method:
Get 10 of described Progesterone vagina expansible plugs, the accurately weighed weight of difference, gently scrape pastille substrate (must not lose cotton sliver), cotton sliver is placed in to the 200-400ml ethanol of 50-80 ℃, preferably, cotton sliver is placed in to the 300ml ethanol of 60-70 ℃, and 80khz frequency ultrasonic cleaning 5 minutes, the remaining stromatolysis in cotton sliver surface is removed, taking out cotton sliver firmly extracts, with filter paper, inhale 3 times again, in 105 ℃, be dried 2 hours, take out, room temperature was placed after 1 hour, the accurately weighed cotton sliver weight of difference, obtain every pastille substrate weight and average pastille substrate weight, every pastille substrate weight and average pastille substrate weight ratio are, what exceed average pastille substrate weight ± 10% must not be more than 2, and must not there is 1 times of 1 overrun.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310750944.6A CN103735492B (en) | 2013-12-31 | 2013-12-31 | Progesterone vaginal expansion plug and preparation method thereof and detection method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310750944.6A CN103735492B (en) | 2013-12-31 | 2013-12-31 | Progesterone vaginal expansion plug and preparation method thereof and detection method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103735492A true CN103735492A (en) | 2014-04-23 |
| CN103735492B CN103735492B (en) | 2016-01-13 |
Family
ID=50492613
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310750944.6A Active CN103735492B (en) | 2013-12-31 | 2013-12-31 | Progesterone vaginal expansion plug and preparation method thereof and detection method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103735492B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104983671A (en) * | 2015-06-30 | 2015-10-21 | 哈尔滨欧替药业有限公司 | Recombinant human granulocyte macrophage colony stimulating factor vaginal expansive suppository and preparation method and detection method thereof |
| CN110384706A (en) * | 2018-04-17 | 2019-10-29 | 上海普特生物科技有限公司 | A kind of Female Sexual Hormones pharmaceutical composition drug delivery system |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103181889A (en) * | 2012-11-29 | 2013-07-03 | 哈尔滨欧替药业有限公司 | Expandable vaginal suppository |
| CN103284941A (en) * | 2013-05-17 | 2013-09-11 | 哈尔滨欧替药业有限公司 | Expansion suppository of clotrimazole or salt thereof, preparation method and detection method |
-
2013
- 2013-12-31 CN CN201310750944.6A patent/CN103735492B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103181889A (en) * | 2012-11-29 | 2013-07-03 | 哈尔滨欧替药业有限公司 | Expandable vaginal suppository |
| CN103284941A (en) * | 2013-05-17 | 2013-09-11 | 哈尔滨欧替药业有限公司 | Expansion suppository of clotrimazole or salt thereof, preparation method and detection method |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104983671A (en) * | 2015-06-30 | 2015-10-21 | 哈尔滨欧替药业有限公司 | Recombinant human granulocyte macrophage colony stimulating factor vaginal expansive suppository and preparation method and detection method thereof |
| CN104983671B (en) * | 2015-06-30 | 2018-11-02 | 哈尔滨欧替药业有限公司 | Recombined human granulocyte-macrophage stimulating factors vaginal expansion plug and preparation method thereof and detection method |
| CN110384706A (en) * | 2018-04-17 | 2019-10-29 | 上海普特生物科技有限公司 | A kind of Female Sexual Hormones pharmaceutical composition drug delivery system |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103735492B (en) | 2016-01-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103720640B (en) | Povidone iodine vaginal expansible plug and preparation method thereof and detection method | |
| CN103784390B (en) | Secnidazole vaginal expansion plug and preparation method thereof and detection method | |
| CN103751094A (en) | Ornidazole vaginal expansion suppository and preparation and detection methods thereof | |
| CN103735492B (en) | Progesterone vaginal expansion plug and preparation method thereof and detection method | |
| CN103751267B (en) | Radix sophorae flavescentis vaginal expansion suppository and preparation and detection methods thereof | |
| CN103536612B (en) | Nifuratel-nystatin expandable vaginal expansible plug and preparation method thereof and detection method | |
| CN103520604A (en) | Baicao expandable vaginal suppository for clearing gynecologic inflammation, and preparation method and detection method thereof | |
| CN103536592B (en) | Metronidazole-furazolidone vaginal expandable suppository and its preparation method and detection method | |
| CN103494767B (en) | Estriol vaginal expansion suppository as well as preparation method and detection method thereof | |
| CN103520086A (en) | Miconazole nitrate expandable vaginal suppository, and preparation method and detection method thereof | |
| CN103520264A (en) | Fukang expandable vaginal suppository, and preparation method and detection method thereof | |
| CN103520380A (en) | Callicarpa nudiflora expandable vaginal suppository, and preparation method and detection method thereof | |
| CN103768005B (en) | Ketoconazole vaginal expansible plug and preparation method thereof and detection method | |
| CN103520240B (en) | Female clean vaginal expansion plug and preparation method thereof and detection method | |
| CN103520088B (en) | Nystatin expandable vaginal expansible plug and preparation method thereof and detection method | |
| CN103751097A (en) | Ofloxacin vaginal swelling suppository, as well as preparation method and detection method thereof | |
| CN103735491A (en) | Clindamycin phosphate vaginal expansive suppository as well as preparation method and detection method thereof | |
| CN103520338A (en) | Zhimikang expandable vaginal suppository, and preparation method and detection method thereof | |
| CN103494925A (en) | Compound cottonrose hibiscus effervescent vaginal dilation suppository as well as preparation method and detection method thereof | |
| CN103494768B (en) | Ciclopirox olamine vaginal dilation expansible plug and preparation method thereof and detection method | |
| CN103494896B (en) | Cnidium monnieri and rheum officinale vaginal dilation suppository as well as preparation method and detection method thereof | |
| CN103520635B (en) | Compound zedoary oil expandable vaginal expansible plug and preparation method thereof and detection method | |
| CN103720639B (en) | Dinoprostone vaginal expansion plug and preparation method thereof and detection method | |
| CN103751096A (en) | Carboprost methylate vaginal swelling suppository, as well as preparation method and detection method thereof | |
| CN103720638A (en) | Fenticonazole nitrate vaginal expansive suppository and preparation method and detection method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20211116 Address after: 150040 office building 7, Bohai Third Road, haping road concentration area, Harbin Economic Development Zone, Harbin, Heilongjiang Province Patentee after: Harbin Tianmei Pharmaceutical Co.,Ltd. Address before: 150069 No. 7, Bohai Third Road, Pingfang Industrial Zone, economic and Technological Development Zone, Harbin, Heilongjiang Province Patentee before: HARBIN OT PHARMACEUTICALS Co.,Ltd. Patentee before: Qiu Mingshi |
|
| TR01 | Transfer of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Progesterone vaginal dilation suppository and its preparation and detection method Effective date of registration: 20230908 Granted publication date: 20160113 Pledgee: China Merchants Bank Co.,Ltd. Harbin Branch Pledgor: Harbin Tianmei Pharmaceutical Co.,Ltd. Registration number: Y2023230000075 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |